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1 USDA/ARS Children's Nutrition Research Center, Baylor College of Medicine, Houston, Texas, USA
2 Department of Pediatrics and Pharmacology, University of Alberta, Edmonton, Alberta, Canada
3 Metabolism and Diabetes and Program in Human Molecular Biology and Genetics, University of Utah, Salt Lake City, Utah, USA
* To whom correspondence should be addressed. E-mail: meyoung{at}bcm.edu.
The molecular mechanism(s) responsible for channeling long-chain fatty acids (LCFAs) into oxidative versus non-oxidative pathways is(are) poorly understood in the heart. Intracellular LCFAs are converted to long-chain fatty acyl-CoAs (LCFA-CoAs) by a family of long-chain acyl-CoA synthetases (ACSLs). Cytosolic thioesterase 1 (CTE1) hydrolyzes cytosolic LCFA-CoAs to LCFAs, generating a potential futile cycle at the expense of ATP utilization. We hypothesized that ACSL isoforms and CTE1 are differentially regulated in the heart during physiological and pathophysiological conditions. Using quantitative RT-PCR, we report that the five known acsl isoforms (acsl1, acsl3, acsl4, acsl5, acsl6) and cte1 are expressed in whole rat and mouse hearts, as well as adult rat cardiomyocytes (ARCs). Streptozotocin-induced insulin-dependent diabetes (4 weeks) and fasting (
24h) both dramatically induced cte1 and repressed acsl6 mRNA, with no significant effects on the other acsl isoforms. In contrast, high fat feeding (4 weeks) induced cte1 without affecting expression of the acsl isoforms in the heart. Investigation into the mechanism(s) responsible for these transcriptional changes uncovered roles for peroxisome proliferator-activated receptor 
(PPAR) and insulin as regulators of specific acsl isoforms and cte1 in the heart. Culturing ARCs with oleate (0.1-0.4mM) or the PPAR agonists WY-14,643 (1µM) and fenofibrate (10µM) consistently induced acsl1 and cte1. Conversely, PPAR null mouse hearts exhibited decreased acsl1 and cte1 expression. Culturing ARCs with insulin (10nM) induced acsl6, while specific loss of insulin signaling within the heart (cardiac-specific insulin receptor knockout mice; CIRKO) caused decreased acsl6 expression. Our data expose differential regulation of acsl isoforms and cte1 in the heart, where acsl1 and cte1 are PPAR-regulated genes, while acsl6 is an insulin-regulated gene.
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